Though there are many effective interventions for Major Depressive Disorder (MDD) available, there is significant heterogeneity in treatment response. One obstacle to improved treatment response rates is the lack of biomarkers to predict who will respond to a given treatment. Further, there is a lack of understanding of genetic mediators of both depressive symptoms and treatment response. In the attempt to form links from genes to depressive phenotype, brain activity is a key intermediate between genes and behavior. In MDD, dopamine (DA) systems are of particular interest, as they underlie reward responsivity (or its lack, anhedonia). This proposal will examine relations between neural response to rewards in MDD, allelic variations of candidate genes regulating functional output of DA systems, and response to psychotherapy. Imaging-genetics has been a fruitful approach in basic and clinical cognitive neuroscience but has not yet been applied to understand heterogeneity of psychotherapy response in MDD. Participants will undergo functional neuroimaging during a reward anticipation and feedback task (Monetary Incentive Delay) and will be genotyped for candidate dopamine genes (COMT, DAT1, and others) before initiating a course of Brief Behavioral Activation Treatment for Depression (BATD) psychotherapy. Candidate DA polymorphisms will be examined as predictors of both fronto-striatal reward network activation as well as psychotherapy treatment response. Fronto-striatal reward network activation will be examined further as a mediator of DA polymorphism effects on treatment response. This approach is an important step in a program of research with the ultimate goal of generating and validating imaging genetic models that may ultimately predict response to both pharmacological and psychotherapeutic antidepressant treatments in MDD. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because MDD is a leading cause of disability and is associated with increased risk of mortality. The proposed project will help to determine what patients are most likely to benefit from behavioral activation, an effective psychotherapy for MDD. The proposed research is relevant to the NIMH Strategic Plan to identify risk factors for mental illness across different phases of disease trajectory, especially the identification of predictors of intervention response.